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Structure–activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and CB2

In an eﬀort to improve indole-based CB2 cannabinoid receptor ligands and also to develop SAR for both the CB1 and CB2 receptors, 47 indole derivatives were prepared and their CB1 and CB2 receptor aﬃnities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The eﬀects of these substituents on receptor aﬃnities are discussed and structure–activity relationships are presented. In the course of this work three new highly selective CB2 receptor agonists were identiﬁed, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPcS assays indicated that JWH-151 is a full agonist at CB2, while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naph-thoyl)indoles. Docking studies indicated that the CB1 receptor aﬃnities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB1 receptor.